The effect of various factors including disease and the concentration of protein on the binding of drugs to plasma albumin has been investigated. The binding of drugs to albumin from patients suffering from renal failure or hepatic disease and from neonates was reduced. Studies with phenylbutazone showed that there were reductions in both the number and affinity of binding sites on albumin isolated from patients with either renal failure or hepatic disease. Other studies with phenylbutazone, sulfadiazine and salicylic acid indicated that both the number of binding sites and their affinity decreased as the concentration of albumin increased. Circular dichroism and fluorescence polarization measurements suggested that these results were due to a concentration-dependent association (dimerization) of albumin.